High-throughput morphologic phenotyping of the mouse brain with magnetic resonance histology

The Mouse Biomedical Informatics Research Network (MBIRN) has been established to integrate imaging studies of the mouse brain ranging from three-dimensional (3D) studies of the whole brain to focused regions at a sub-cellular scale. Magnetic resonance (MR) histology provides the entry point for many morphologic comparisons of the whole brain. We describe a standardized protocol that allows acquisition of 3D MR histology (43-μm resolution) images of the fixed, stained mouse brain with acquisition times < 30 min. A higher resolution protocol with isotropic spatial resolution of 21.5 μm can be executed in 2 h. A third acquisition protocol provides an alternative image contrast (at 43-μm isotropic resolution), which is exploited in a statistically driven algorithm that segments 33 of the most critical structures in the brain. The entire process, from specimen perfusion, fixation and staining, image acquisition and reconstruction, post-processing, segmentation, archiving, and analysis, is integrated through a structured workflow. This yields a searchable database for archive and query of the very large (1.2 GB) images acquired with this standardized protocol. These methods have been applied to a collection of both male and female adult murine brains ranging over 4 strains and 6 neurologic knockout models. These collection and acquisition methods are now available to the neuroscience community as a standard web-deliverable service.